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Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications
Megan R Dreier1, Jasmine Walia1, Ivana L de la Serna1
1Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Ave, Toledo 43614, OH, USA.
Abstract:
SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions.
Insights
Targeting SWI/SNF complexes, crucial for DNA repair and transcription, shows promise in cancer therapy. Novel PROTACs degrade specific subunits, advancing drug development from preclinical to clinical trials.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- SWI/SNF enzymes are ATP-dependent chromatin remodelers with vital roles in DNA replication, repair, and transcription.
- Dysregulation of SWI/SNF complexes, including sub-complexes like cBAF, ncBAF, and PBAF, is implicated in various cancers.
- SWI/SNF complexes are attractive targets for cancer drug development due to their critical functions.
Purpose of the Study:
- To review current therapeutic strategies targeting SWI/SNF complexes in cancer.
- To highlight the development and potential of pharmacological agents, including PROTACs, for cancer treatment.
- To assess the progression of SWI/SNF-targeting agents from preclinical research to clinical trials.
Main Methods:
- Review of existing literature on SWI/SNF complex function and therapeutic targeting.
- Analysis of pharmacological agents, including catalytic subunit inhibitors and bromodomain binders.
- Examination of Proteolysis-targeting chimeras (PROTACs) designed for SWI/SNF subunit degradation.
Main Results:
- Inhibitors targeting catalytic subunits (SMARCA4/2) and bromodomains are key strategies.
- PROTACs enhance SWI/SNF inhibition by promoting targeted subunit degradation.
- Preclinical studies demonstrate significant therapeutic potential across diverse cancer types.
Conclusions:
- Targeting SWI/SNF complexes represents a promising avenue for cancer therapy.
- PROTAC technology offers an advanced approach for modulating SWI/SNF function.
- Several SWI/SNF-targeting agents are advancing into clinical trials, indicating therapeutic progress.
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